A Rational Systematic Approach to Identify Combinations of Pharmacologic and Immune Therapies that Target Identifiable Oncogenic States. Abstract Efforts to sequence large number of human cancers have provided a rich catalog of the most common genetic alterations that driven cancer formation and maintenance. This increasingly accurate mutational landscape has led to the identification of novel targets for therapeutic interventions. However, there is widespread biological and clinical heterogeneity in tumors, even when they share the same driver oncogene mutation. In addition, a high degree of dynamic plasticity and adaptability makes cancers display complex patterns of acquired resistance that manifest clinically. In a similar way, the wide variability of clinical responses to immunotherapy and the onset of immune escape, are becoming a formidable obstacle to fully realize the potential of many new and potentially effective immunotherapies. In this project we will evaluate a rational systematic approach to characterize oncogenic states and their most salient genomic and immune hallmarks in order to infer optimal combinations of pharmacologic and immunological perturbagens that disrupt cancer cell and tumor microenvironment interaction and viability. Our approach is based on our preliminary data, which suggests that in each identifiable oncogenic state there is a close interplay between activation of oncogenic elements, cellular pathways and the immune microenvironment. The project will test this approach with three Specific Aims: Aim 1. Characterize 5-10 pan-cancer oncogenic states with well-defined genomic and immune hallmarks including their specific molecular targets and sensitivity to perturbagens. Aim 2. Computationally infer optimal combinations of pharmacological and immunological perturbagens. Aim 3. Experimentally validate single and combinations of perturbagens identified in Aim 2. This innovative approach will provide a rich source of CTD2 datasets and resources including a catalog of oncogenic states, their most salient genomic and immune hallmarks, associated targets and validated combinations of pharmacologic and immune therapies that are effective at targeting tumors. These results will lead directly to the development of clinical trials, novel treatment strategies and provide the foundation for a new generation of more comprehensive, functional-based, precision medicine approaches.